The bone is the most common site of metastasis in patients with advanced cancers including breast and prostate cancers (Jin et al. (2011) Int. J. Cancer 128, 2545-2561; Kohno, (2008) Int. J. Clin. Oncol. 13, 18-23). Bone metastases are major, potentially fatal complications in patients with advanced cancers. Almost all patients with skeletal metastases have significantly decreased quality of life due to intense pain, pathological fractures, spinal cord compression, and metabolic complications (Welch et al. (2003) J. Musculoskelet. Neuronal Interact. 3, 30-38). In fact, post-mortem studies have shown that over 70% of breast cancer patients exhibited skeletal metastases, and only 20% of these patients are still alive five years after the discovery of the metastases (Roodman (2004) N. Engl. J. Med. 350, 1655-1664; Welch et al. (2003) J. Musculoskelet. Neuronal Interact. 3, 30-38). The high affinity that cancer has for bone is explained by the “seed-and-soil hypothesis”, which was proposed over a century ago (Paget (1889) Lancet 1, 571-573). It reveals that bone tissues are preferred sites of cancer metastasis due to their microenvironment, which provides a fertile setting in which tumor cells can grow. Many features, such as increased blood flow as well as the release of growth factors from cells in the bone matrix, account for the frequency of bone metastases (van der Pluijm et al. (2001) J. Bone Miner. Res. 16, 1077-1091). Thus far, the critical factors and mechanisms responsible for bone metastases are largely unknown.
Bisphosphonate drugs are used to treat bone cancer metastasis and result in decreased tumor growth, reduced bone destruction, and reduced pain (Brown and Guise (2007) Cur. Osteopor. Rep. 5, 120-127). Bisphosphonate therapy is associated with adverse side effects, which include atrial fibrillation; arthralgia and osteonecrosis of the jaw; and ophthalmic, dermatologic and renal complications; as well as medication-induced fractures (Junquera et al. (2009) Am. J. Otolaryngol. 30, 390-395; Truong et al. (2010) J. Am. Acad. Dermatol. 62, 672-676). Despite advances in the diagnosis and treatment of bone metastasis from solid tumors, the mechanism of how bisphosphonate treatment inhibits bone metastasis at the molecular level remains to be established.
Previous studies point to the possibility that ATP through its binding to P2 purinergic receptors exhibits an anti-cancer effect (White and Burnstock (2006) Trends Pharmacol. Sci. 27, 211-217). Several studies have established the anti-neoplastic activity of ATP to inhibit the growth of several cell lines, including prostate cancer cells, colon adenocarcinoma cells, melanoma cells, and bladder cancer cells (Rapaport et al. (1983) Cancer Res. 43, 4402-4406; Shabbir and Burnstock (2009) Int. J. Urol. 16, 143-150; White and Burnstock (2006) Trends Pharmacol. Sci. 27, 211-217). The activation of purinergic signaling is also reported to inhibit proliferation and migration of human acute myeloblastic leukemia cells in immune-deficient mice (Salvestrini et al. (2012) Blood 119, 217-226). Additionally, in vivo studies show that daily injections of ATP significantly inhibit tumor growth, prolong survival time, and inhibit weight loss in mice (Rapaport (1988) Eur. J. Cancer Clin. Oncol. 24, 1491-1497). However, several studies also suggest adverse effects of ATP including increased tumor growth and migration. We recently reported that ATP and ATP analog such as ATPγS inhibits breast cancer cell growth migration and bone metastasis, whereas adenosine and activation of adenosine receptors have opposite effects by promoting growth, migration, and bone metastasis of breast cancer cells (Zhou et al. (2014) Oncogene (Epub)).
Non-hydrolysable ATP analog compounds and adenosine receptor antagonist analog compounds can be used for treatment of cancer (WO2014074529). However, there still remains a need for additional non-hydrolysable ATP analog compounds and adenosine receptor antagonists.